1. Field of the Invention
The invention relates to novel porphycene compounds and pharmaceutical compositions containing these compounds which are useful for therapeutic treatment.
2. Discussion of the Background
During the past few years there has developed a widespread recognition that modern, though sophisticated, cancer diagnosis and treatments have served neither to reduce overall the number of cases of reported cancers in the U.S.A. nor, save the notable cases, the death rate. This is a disheartening result for the billions of dollars invested in conquering the disease. Moreover, surgery, radiotherapy and chemotherapy are all associated with major debilitating side effects such as trauma, severe immunosuppression or toxicity which are not easily surmounted by patients already compromised by ill-health.
Early work in the 1970's, followed by rapidly expanding studies in the 1980's, has shown that photodynamic therapy (PDT) offers a viable, less toxic and generally less painful avenue to treatment of cancer. Not all cancers are candidates for PDT. However, neoplasms of hollow organs and skin, including multifocal carcinoma in situ, sometimes inoperable, and with no good track record for treatment by established therapeutic procedures, appear to be targets for PDT.
In photodynamic therapy, porphyrinoid dyes are administered to a patient and localize in neoplastic tissues (Lipson et al., J. Thoracic Cardiovascular Surgery, 1961, 42:623-629). Irradiation of the porphyrinoid dye with light at a wavelength which corresponds to an absorption band of the dye results in destruction of the neoplastic tissue. See also Kessel, D., "Methods in Porphyrin Photosensitization", Plenum Press, New York, 1985; Gomer, C. J., "Photodynamic Therapy", Pergammon Press, Oxford, 1987 and Doiron, D. R. and Gomer, C. J., "Porphyrin Localization and Treatment of Tumors", Liss, New York, 1984. The use of a fiber optic laser light source is described in U.S. Pat. No. 4,957,481.
Dougherty et al. (Cancer Res., 1978, 38:2628; Photochem. Photobiol, 1987, 45:879) pioneered the field with infusion of photoactivatable dyes, followed by appropriate long wavelength radiation of the tumors (600+nm) to generate a lethal short-lived species of oxygen which destroyed the neoplastic cells. Early experiments utilized a mixture termed hematoporphyrin derivative (HPD). See also Lipson et al., J.N.C.I., 1961, 26:1; Dougherty et al., J.N.C.I., 1975, 55:115; Diamond et al., Lancet, 1972(II), 1175; D. Dolphin, "The Porphyrin", vol. I, Academic Press, New York, 1978; and D. Kessel, Photochem. Photobiol., 1984, 39:851. The deficiencies of HPD, especially prolonged phototoxicity caused by retained HPD components in human skin led to its displacement by a purified fraction initially termed dihematoporphyrin ether (DHE), and later marketed by QuadraLogics Technologies as the commercial product "PHOTOFRIN", which, although yielding improvements over HPD, nevertheless still suffered certain practical limitations. Relatively weak absorption in the wavelength range above 600 nm, retention in dermal cells (potentially leading to phototoxicity), only modest or low selectivity for tumor cells versus other cell types in vital organs, the inability to use available, modern, inexpensive diode lasers, and uncertain chemical constitution of the mixtures are all known negative features of PHOTOFRIN and HPD. The great majority of the earlier PDT agents studied have been derived from natural sources (porphyrin, chlorins, purpurins, etc.) or from known chemicals originating in the dyestuffs industry (e.g., cyanine dyes). For more recent PDT agents derived from natural sources see U.S. Pat. No. 4,961,920 and U.S. Pat. No. 4,861,876.
In animal and cell culture experiments one observes, following PDT, depending on the incubation time, damage to the vasculature, cell membranes, mitochondria and specific enzymes. When absorbed in tumor cells, an increased selectivity can be obtained by injecting the porphyrinoid sensitizers enclosed in liposomes (Ricchelli and Jori, Photochem. Photobiol., 1986, 44:151). Porphyrinoid dyes can be transported in the blood with the aid of lipoproteins such as low-density lipoprotein (Jori et al., Cancer Lett., 1984, 24:291).
PDT has been used to treat bladder, bronchial, bone marrow and skin tumors (Dougherty, Photochem. Photobiol., 1987, 45:879, Sieber et al., Leukemia Res., 1987, 11:43) as well as severe psoriasis (Diezel et al., Dermatol. Monatsschr., 1980, 166:793; Emtenstam et al., Lancet, 1989 (I), 1231). Treatment of viruses in transfused blood has also been reported (Matthews et al., Transfusion, 1988, 28.81; Sieber et al., Semin. Hematol., 1989, 26:35).
As the deficiencies of earlier PDT agents have become apparent, it also becomes possible to define activity parameters for improved chemically pure photoactivatable dyes for PDT therapy, available by chemical synthesis. Moreover, the products of synthesis lend themselves more readily to further chemical structural manipulation than do the naturally occurring starting materials which can be expensive and bear chemically sensitive constituents. The synthesis of novel porphycene macrocycles embracing four pyrrole rings has been described by Vogel and coworkers. Alkylated porphycenes have also been prepared (R=Me, Et, n-Pr, tert. butyl, phenyl) and the photochemical properties determined. The potential suitability of these compounds for PDT was noted and confirmed in animal studies (Guardiano et al., Cancer Letters, 1989, 44, 1).
Synthetic efforts have focused on porphryinoid compounds which are highly absorptive in the longer wavelength range of about 660-900 nm, where the transparency of tissue is higher. compounds such as purpurines (Morgan et al., J. Org. Chem., 1986, 51:1347; Morgan et al., Cancer Res., 1987, 47:496; Morgan et al., J. Med. Chem., 1989, 32:904; Hoober et al., Photochem. Photobiol., 1988, 48:579), naphthocyanin silicon complexes (Firey et al., J. Am. Chem. Soc., 1988, 110:7626), chlorins (Robert et al., J.N.C.I., 1988, 80:330; Kessel, Cancer Res., 1986, 46:2248), bacteriochlorins (Beams et al., Photochem. Photobiol., 1987, 46:639) and substituted phenylporphyrins (Kreimer-Birnbaum, Semin. Hematol., 1989, 26:157) have been prepared and tested in vivo. Additional PDT agents are described in EP 276,121.
Pyrrole-containing ring systems larger than porphycene have also been prepared and evaluated as photosensitizers. Sessler et al. have prepared and studied texaphyrin (J. Am. Chem. Soc., 1988, 110:5586) and Woodward et al. and Johnson et al. have prepared and investigated the sapphyrin ring system. Additionally, the platyrin system has been studied by LeGoff (Tetrahedron, Lett., 1978, 4225; J. Org. chem., 1987, 710) and vinylogous porphyrins have been studied by Franck (Angew. Chem., 1986, 98:1107; Angew. Chem. Int. Ed. Eng., 1986, 25:1100; Angew. Chem., 1988, 100:1203; Angew. Chem. Int. Ed. Eng., 1988, 27:1170).
A need continues to exist, therefore, for new compounds for use in PDT therapy, which compounds are easily available, have low intrinsic toxicity, are efficient photosensitizers for single oxygen production, have selective uptake in rapidly proliferating cells, are rapidly or at least moderately rapidly degraded and eliminated from the tissues after administration and which are available as chemically pure and stable compounds easily subject to synthetic modification. The compound should be capable of formulation to allow transdermal delivery if targeted for topical application.